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Ferlins Show Tissue-Specific Expression and Segregate as Plasma Membrane/Late Endosomal or Trans-Golgi/Recycling Ferlins

Journal Article


Abstract


  • Ferlins are an ancient family of Ca2+-binding, multi-C2 domain vesicle fusion proteins. Of the six human ferlins, mutations in dysferlin cause muscular dystrophy and otoferlin cause deafness. We detail the tissue-distribution, subcellular localization and endocytic trafficking of the human ferlins. Dysferlin and myoferlin, type-I ferlins, localize to the plasma membrane and late endosomes, which display potential for occasional recycling. Otoferlin and Fer1L6, type-II ferlins, localize to dedicated recycling subcompartments of the trans-Golgi network. We establish that type-I and type-II ferlins segregate into late-endosomal and recycling trans-Golgi compartments. Ferlins are a family of transmembrane-anchored vesicle fusion proteins uniquely characterized by 5-7 tandem cytoplasmic C2 domains, Ca2+-regulated phospholipid-binding domains that regulate vesicle fusion in the synaptotagmin family. In humans, dysferlin mutations cause limb-girdle muscular dystrophy type 2B (LGMD2B) due to defective Ca2+-dependent, vesicle-mediated membrane repair and otoferlin mutations cause non-syndromic deafness due to defective Ca2+-triggered auditory neurotransmission. In this study, we describe the tissue-specific expression, subcellular localization and endocytic trafficking of the ferlin family. Studies of endosomal transit together with 3D-structured illumination microscopy reveals dysferlin and myoferlin are abundantly expressed at the PM and cycle to Rab7-positive late endosomes, supporting potential roles in the late-endosomal pathway. In contrast, Fer1L6 shows concentrated localization to a specific compartment of the trans-Golgi/recycling endosome, cycling rapidly between this compartment and the PM via Rab11 recycling endosomes. Otoferlin also shows trans-Golgi to PM cycling, with very low levels of PM otoferlin suggesting either brief PM residence, or rare incorporation of otoferlin molecules into the PM. Thus, type-I and type-II ferlins segregate as PM/late-endosomal or trans-Golgi/recycling ferlins, consistent with different ferlins mediating vesicle fusion events in specific subcellular locations.

Publication Date


  • 2016

Citation


  • Redpath, G. M. I., Sophocleous, R. A., Turnbull, L., Whitchurch, C. B., & Cooper, S. T. (2016). Ferlins Show Tissue-Specific Expression and Segregate as Plasma Membrane/Late Endosomal or Trans-Golgi/Recycling Ferlins. Traffic, 17(3), 245-266. doi:10.1111/tra.12370

Scopus Eid


  • 2-s2.0-84959061752

Start Page


  • 245

End Page


  • 266

Volume


  • 17

Issue


  • 3

Abstract


  • Ferlins are an ancient family of Ca2+-binding, multi-C2 domain vesicle fusion proteins. Of the six human ferlins, mutations in dysferlin cause muscular dystrophy and otoferlin cause deafness. We detail the tissue-distribution, subcellular localization and endocytic trafficking of the human ferlins. Dysferlin and myoferlin, type-I ferlins, localize to the plasma membrane and late endosomes, which display potential for occasional recycling. Otoferlin and Fer1L6, type-II ferlins, localize to dedicated recycling subcompartments of the trans-Golgi network. We establish that type-I and type-II ferlins segregate into late-endosomal and recycling trans-Golgi compartments. Ferlins are a family of transmembrane-anchored vesicle fusion proteins uniquely characterized by 5-7 tandem cytoplasmic C2 domains, Ca2+-regulated phospholipid-binding domains that regulate vesicle fusion in the synaptotagmin family. In humans, dysferlin mutations cause limb-girdle muscular dystrophy type 2B (LGMD2B) due to defective Ca2+-dependent, vesicle-mediated membrane repair and otoferlin mutations cause non-syndromic deafness due to defective Ca2+-triggered auditory neurotransmission. In this study, we describe the tissue-specific expression, subcellular localization and endocytic trafficking of the ferlin family. Studies of endosomal transit together with 3D-structured illumination microscopy reveals dysferlin and myoferlin are abundantly expressed at the PM and cycle to Rab7-positive late endosomes, supporting potential roles in the late-endosomal pathway. In contrast, Fer1L6 shows concentrated localization to a specific compartment of the trans-Golgi/recycling endosome, cycling rapidly between this compartment and the PM via Rab11 recycling endosomes. Otoferlin also shows trans-Golgi to PM cycling, with very low levels of PM otoferlin suggesting either brief PM residence, or rare incorporation of otoferlin molecules into the PM. Thus, type-I and type-II ferlins segregate as PM/late-endosomal or trans-Golgi/recycling ferlins, consistent with different ferlins mediating vesicle fusion events in specific subcellular locations.

Publication Date


  • 2016

Citation


  • Redpath, G. M. I., Sophocleous, R. A., Turnbull, L., Whitchurch, C. B., & Cooper, S. T. (2016). Ferlins Show Tissue-Specific Expression and Segregate as Plasma Membrane/Late Endosomal or Trans-Golgi/Recycling Ferlins. Traffic, 17(3), 245-266. doi:10.1111/tra.12370

Scopus Eid


  • 2-s2.0-84959061752

Start Page


  • 245

End Page


  • 266

Volume


  • 17

Issue


  • 3